Molecules involved in immune cell signaling can have independent functions in the central nervous system. Such molecules may have dual roles in cellular therapy where neural progenitor cells are transplanted into the active immune signaling environment of the diseased or injured brain. Class I major histocompatibility complex (MHC1) molecules are prominent examples with well defined function in both allograft rejection and in neurodevelopment. In addition to mediating antigen presentation by immune cells, MHC1 and cognate receptors are expressed by neurons and influence axonal growth and synapse formation and elimination. MHC expression in neurons is also pathologically up-regulated by immune cytokines present in the injured or degenerating brain. This proposal examines both immunological and neurodevelopmental roles of MHC1 in transplantation. Allogeneic cell or tissue transplants are being used in numerous clinical settings and while purified allogeneic cells can survive well in the CNS, we have found that neuron abundance in neural progenitor cell grafts is significantly reduced relative to syngeneic grafts. This may be due to the selective elimination of MHC-expressing neurons by an allo-specific T cells but classical immunosuppression does not alter outcome. In contrast, we find that attenuating innate immune signaling and cytokine production is more effective and can increase the abundance of allogeneic neurons to levels approaching syngeneic grafts. This highlights a growing awareness that T cell mediated graft rejection is only one variable in a more complex immunological equation that influences the function of graft-derived neurons in cellular therapy. The immune mechanisms may be diverse but historical data highlights the relative importance of class I MHC in both immune recognition and neurodevelopment. Experiments in this proposal focus on defining the specific roles of MHC1 in classical innate and adaptive immune recognition as well as the non-immunological roles in neuron connectivity and survival following transplant to the adult brain. PUBLIC HEALTH RELEVANCE: There is growing interest in the use of stem cells or neural progenitor cells in neurological therapy. Allogeneic cell or tissue transplants are being used in numerous clinical settings and while purified allogeneic cells can survive well in the CNS, we have found that neuron abundance in neural progenitor cell grafts is impacted by immune signaling mechanisms beyond those addressed with immunosuppressive drugs. Experiments in this proposal focus on defining the specific roles of classical innate and adaptive immune recognition as well as the non-immunological roles of neuronal class I MHC molecules in altering neural progenitor cell survival and connectivity following transplantation in models of stem cell reconstitution and neuron replacement in Parkinson's disease.